All diagnostic imaging is based on the achievement of different signal levels from different structures within the body so that these structures can be seen. Thus in X-ray imaging for example, for a given body structure to be visible in the image, the X-ray attenuation by that structure must differ from that of the surrounding tissues. The difference in signal between the body structure and its surroundings is frequently termed contrast and much effort has been devoted to means of enhancing contrast in diagnostic imaging since the greater the contrast or definition between a body structure or region of interest and its surroundings the higher the conspicuity or quality of the images and the greater their value to the physician performing the diagnosis. Moreover, the greater the contrast the smaller the body structures that may be visualized in the imaging procedures, i.e. increased contrast can lead to increased discernable spatial resolution and conspicuity.
The diagnostic quality of images is strongly dependent on the inherent noise level in the imaging procedure, and the ratio of the contrast level to the noise level or definition between contrast and noise can thus be seen to represent an effective diagnostic quality factor for diagnostic images. Achieving improvement in such a diagnostic quality factor has long been and still remains an important goal whilst keeping the patient safe, especially from excessive radiation. In techniques such as X-ray imaging one approach to improving the diagnostic quality factor has been to introduce contrast enhancing materials formulated as contrast media into the body region being imaged.
Thus in X-ray early examples of contrast agents were insoluble inorganic barium salts which enhanced X-ray attenuation in the body zones into which they distributed. For the last 50 years the field of X-ray contrast agents has been dominated by soluble iodine containing compounds. Commercial available contrast media containing iodinated contrast agents are usually classified as ionic monomers such as diatrizoate (marketed e.g. under the trade mark Gastrografen™), ionic dimers such as ioxaglate (marketed e.g. under the trade mark Hexabrix™), non-ionic monomers such as iohexol (marketed e.g. under the trade mark Omnipaque™), iopamidol (marketed e.g. under the trade mark Isovue™), iomeprol (marketed e.g. under the trade mark Iomeron™) and the non-ionic dimer iodixanol (marketed under the trade mark Visipaque™).
The most widely used commercial non-ionic X-ray contrast agents such as those mentioned above are considered safe for clinical use. Contrast media containing iodinated contrast agents are used in more than 20 million of X-ray examinations annually in the USA and the number of adverse reactions is considered acceptable. However, there is still a need for improved methods for X-ray, and CT images, providing increased safety and high-quality images. This need is more apparent in patients/subjects with pre-existing diseases and conditions or immature/low renal function. This is because certain diseases and low renal function increase the chance of adverse reactions to injected iodinated contrast media. Pre-existing diseases of concern include lung disease, kidney disease, heart disease, liver disease, inflammatory disease, autoimmune disease and other comorbidities e.g. metabolic disorders (diabetes, hyperlipidaemia, hyperinsulinaemia, hypercholestraemia, hypertriglyceridaemia and hypertension), cardiovascular disease, peripheral vascular disease, atherosclerosis, stroke and congestive heart failure. Furthermore a subject's age is important since a greater number of adverse events are reported in the elderly, while immature renal function, as can be found in young children and infants, can also lead to prolonged circulation of contrast media and a greater number and intensity of adverse reactions.
The risk of adverse events is not limited to the effects of contrast media. Radiation associated with CT accounts for about 70-75% of the total ionizing radiation from diagnostic imaging. While these levels of radiation are well below those that cause deterministic effects (for example, cell death), there is concern that they may be associated with a risk of stochastic effects (such as cancer, cataracts and genetic effects). Those at greatest risk for developing radiation exposure-related cancer later in life are children and women in their 20s, and according to Hall E J. Ped Radiol 2002; 32: 225-7 are children 2-10 times more sensitive to radiation than adults. Approximately 33% of all paediatric CT examinations are performed in children in the first decade of life, with 17% in children at or under the age of 5 years. Exposure to radiation at an early age carries a risk because organs and tissues in children are more sensitive to the effects of radiation than those of an adult and they have a longer remaining life expectancy in which cancer may potentially form. Brenner D et al. N Engl J Med 2007; 357: 2277-83 reports that the risk of death from cancer exists after only a single CT scan, and although low, this risk is considerably higher for children and young people. In addition, the current prevalence of CT makes it more likely that children will receive a higher cumulative lifetime dose of medically related radiation than those who are currently adults.
Since such contrast media are conventionally used for diagnostic purposes rather than to achieve direct therapeutic effect or provide a patient benefit, it is generally desirable to provide contrast media having as little as possible effect on the various biological mechanisms of the cells or the body as this will lead to lower toxicity and lower adverse clinical effect. The toxicity and adverse biological effects of iodinated contrast media are contributed to by the components of the formulation medium, e.g. the solvent, carrier, buffers or chelators as well as the contrast agent itself and its components such as ions for the ionic contrast agents, and also by its metabolites.
The major contributing factors to the toxicity of the contrast medium are identified as the chemotoxicity of the iodinated contrast agent structure and its physicochemistry, especially the osmolality of the contrast medium and the ionic composition or lack thereof of the contrast medium formulation. Desirable characteristics of an iodinated contrast agent have been considered to be low toxicity of the compound itself (chemotoxicity), low osmolality of the contrast medium, high hydrophilicity (solubility) and a high iodine content, frequently measured in mg iodine per ml (mg I/ml) of the formulated contrast medium for administration. The iodinated contrast agent must also be completely soluble in the formulation medium, usually an aqueous medium, and remain in solution during storage and administration.
The osmolalities of the commercial products, and in particular of the non-ionic compounds, is acceptable for most media containing dimers and non-ionic monomers although there is still room for improvement. In coronary angiography for example, injection into the circulatory system of a bolus dose of contrast medium may cause severe side effects. In this procedure, immediately after injection contrast medium rather than blood flows through the system for a short period of time, and differences in the chemical and physiochemical nature of the contrast medium and the blood that it replaces can cause undesirable adverse effects such as arrhythmias, prolongation of the QT interval of the heart's electrical cycle, reduction in cardiac contractive force, reduction in oxygen carrying capacity of blood cells and tissue ischemia of the organ in which high levels of contrast media are present. Such effects are seen in particular with ionic contrast agents where chemotoxic and osmotoxic effects are associated with hypertonicity of the injected contrast medium. Contrast media that are isotonic or slightly hypotonic with the body fluids are particularly desired. Hypoosmolar contrast media have low renal toxicity which is particularly desirable.
In patients with acute renal failure, nephropathy induced by contrast medium remains one of the most clinically important complications of the use of iodinated contrast medium. Aspelin, P et al, The New England Journal of Medicine, Vol. 348:491-499 (2003) concluded that nephropathy induced by contrast medium may be less likely to develop in high risk patients when iodixanol, a hypoosmolar agent made isoosmolar with blood due to the addition of plasma electrolytes, is used rather than a low-osmolar, non-ionic contrast medium. These findings have later been reinforced by others, showing that Iodine contrast media osmolality is the key driver of contrast induced nephrotoxicity (CIN) and contrast media induced acute kidney injury.
The portion of the patient population considered as high-risk patients is increasing e.g. due to higher expected average age. To meet the need for continuous improvement of in vivo X-ray diagnostic agents for the entire patient population, there is a continuous drive in finding X-ray contrast agents and methods for x-ray imaging wherein the patient safety is optimized.
To keep the injection volume of the contrast media low it has been desirable to formulate contrast media with high concentration of iodine/ml, and still maintain the osmolality of the media at a low level, preferably below or close to isotonicity. This thinking corresponds to the notion that a higher iodine concentration may provide better diagnosis. The development of non-ionic monomeric contrast agents and in particular non-ionic bis(triiodophenyl) dimers such as iodixanol (EP 108638) has provided contrast media with reduced osmotoxicity. This has allowed contrast with effective iodine concentration to be achieved with hypotonic solution, and has even allowed correction of ionic imbalance by inclusion of plasma ions while still maintaining the contrast medium at the desired osmolality, e.g. as for Visipaque™.
However, to reduce the risk of adverse events, especially in susceptible subjects, to improve patient safety and to reduce costs, there is now a desire to reduce the amount (volume and iodine dose) of X-ray contrast media administered to patients undergoing X-ray examinations.
WO 2009/008734 of GE Healthcare AS discloses a new class of compounds and their use as X-ray contrast agents. The compounds are dimers containing two linked iodinated phenyl groups. The bridge linking the two iodinated phenyl groups is a straight C3 to C8 alkylene chain optionally substituted by one to six —OH or OCH3 groups. A range of compounds are covered by the general formula (I) of the application and many specific compounds are suggested. Compound I, which is one specific dimeric X-ray contrast agent, falling within the formula I of WO2009/008734, given the International Non-proprietary name Ioforminol, has been found by the applicant to have particularly favourable properties. Compound I is 5,5′-((2-hydroxypropane-1,3-diyl)bis(formylazanediyl))bis(N1,N3-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide).